A number of imidazole antimycotic agents are under investigation or are used for the treatment of dermatomycoses (an infection of the skin caused by dermatophytes or other fungi) or onychomycosis (a fungal infection of the nail plate and/or nail bed). One such antimycotic agent approved and launched in Japan for cutaneous mycosis such as Tinea pedis, tinea corporis and tinea cruris as well as Candidiasis and Tinea versicolor infection is luliconazole (Lulicon® Cream and Solution 1%).
The compound luliconazole is represented by the formula (I):

Luliconazole is a compound screened from analogues of its predecessor lanoconazole, which has been clinically used for the treatment of dermatomycoses. It is believed that luliconazole produces its antifungal effect by inhibiting the synthesis of ergosterol, which is a constituent of the cell membrane of fungi. The antifungal activity of luliconazole was recently tested against clinically important dermatomycotic fungi and compared to other representative antifungal reference drugs. Luliconazole demonstrated greater potency against Trichophyton rubrum, Trichophyton mentagrophytes and Trichophyton tonsurans than the reference drugs, such as allylamine (terbinafine), thiocarbamate (liranaftate), benzylamine (butenafine), morpholine (amorolfine), and azoles (ketoconazole, clotrimazole, neticonazole, miconazole and bifonazole). Koga et al., Med. Mycol. (2008) 1-8.
The concentration of luliconazole in a stable cream is found in the commercial product Lulicon® at 1% by weight. Creams and other liquid formulations containing luliconazole have been described as having about 0.5% to about 5% by weight luliconazole. See, e.g., U.S. Patent Publication Nos. US2009/0137651, published May 28, 2009; US2009/0076109, published Mar. 19, 2009; and US2009/0030059, published Jan. 29, 2009. Creams and other liquid formations containing greater than 5% luliconazole are known to be unstable and difficult to solubilize, resulting in crystallization or precipitation of the compound out of solution. Nonetheless, there remains a need for such formulations, e.g., for use in the treatment of dermatomycoses and onychomycosis.
Tinea pedis, also known as athlete's foot, is the most common of the dermatomycoses, affecting up to 10 percent of the general population. However, onychomycosis, which accounts for up to 50% of all nail diseases and affects approximately 35 million people in the U.S. alone, is much more difficult to treat than Tinea pedis, for several reasons, such as the site of infection, time required to regenerate healthy nail, and the composition of a nail as compared to the skin. Dandah, M. J. et al., (2006) U.S. Dermatology Review 1-4. As a result, formulations that are sufficient in the treatment of Tinea pedis are not generally sufficient for the treatment of onychomycosis.
The site of fungal infection in onychomychosis makes its treatment particularly challenging. Distal subungual onychomycosis (DSO), which is the most common form of onychomycosis, is characterized by fungal invasion of the nail bed and underside of the nail plate beginning at the hyponychium. Clinical findings associated with DSO include nail discoloration (yellowing or other discoloration such as the presence of black or brown color), thickening, subungual debris and loss of attachment of the nail plate to the nail bed. The nail may also become friable and crumble away. DSO can cause extreme nail disfigurement and often results in pain. Treatment of the infected region with a topical pharmaceutical composition requires the composition to deliver a therapeutically effective amount of the active agent through the nail in order to reach the site of infection. The only U.S. Food and Drug Agency approved topical treatment for onychomycosis is ciclopirox (Penlac®, Dermik) an 8% topical solution applied as a nail lacquer. In De Berker, N. Engl. J. Med. (2009)360: 2108-16, the mycologic cure for DSO using Penlac daily for 48 weeks was reported to be 28 to 36%. However, a clear nail was achieved in only 7% of cases. Amorolfine (Loceryl®, Galderma) is another topical therapy that has long treatment times and low cure rates, likely as a result of poor drug penetration through the nail. De Berker, supra. Topical therapeutics for onychomycosis thus fail to provide optimal treatment of the infection site. Orally administered drugs are an alternative to topical treatments for onychomycosis, but have their own disadvantages, including prolonged systemic exposure to an active agent when only a specific site is infected. Ketoconazole (Nizoral®, Janssen-Cilag) was the first oral imidazole introduced for the treatment of onychomycosis in the 1980s. However, due to hepatotoxicity its use is now restricted to nail infections that have failed to respond to other therapies. Griseofulvin (Grisovin®, Glaxo Welcome) is an oral therapeutic that has been available since the 1950s which results in low cure and high relapse rates. Elewski, B. E., Clinical Microbiology Reviews (1998)11:415-429. The newer oral anti-fungals, terbinafine (Lamisil®) and itraconazole (Sporanox®) are effective in the treatment of onychomycosis with mycological cure rates of 70-80% and treatment periods of 12-16 weeks. However, even in the newer oral anti-fungals, the percentage of patients exhibiting both mycological cure and clinical cure remain low. For example, in a study of patients being treated for onychomycosis of the toenail with Lamisil®, only 38% of patients treated demonstrated both mycological cure (simultaneous occurrence of negative KOH plus negative culture) and clinical cure (0% nail involvement). See Lamisil® Package Insert. In a study of patients being treated for onychomycosis of the toenail with Sporanox®, only 14% of patients treated demonstrated both mycological cure and clinical cure. See Sporanox® Package Insert. These drugs also have significant side effects and interact with many medications, which limits their use. For example, liver failure requiring liver transplant or resulting in death have occurred in patients, with and without preexisting liver disease, taking oral Lamisil® for the treatment of onychomycosis. In addition, Lamisil® is known to inhibit CYP450 2D6 isozyme. Drugs that are predominately metabolized by the CYP450 2D6 isozyme include tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics class 1C and monoamino oxidase inhibitors type B, and individuals who are taking one or more of these medications concurrently with Lamisil® must be carefully monitored and may require a reduction in dosage of such drugs. Sporanox® has been associated with cases of serious hepatotoxicity, including liver failure and death, with certain instances occurring in individuals having neither pre-existing liver disease or a serious underlying medical condition. Sporanox®, which is an inhibitor of CYP3A4, is also contraindicated in patients with evidence of ventricular dysfunction, such as patients with congestive heart failure and in patients taking cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with Sporanox® and/or other CYP3A4 inhibitors. Thus, oral therapies do not provide sufficient or effective cure rates, are associated with series adverse side affects and limited in their application. A significant unmet medical need remains for an effective treatment of onychomycosis. A treatment that has fewer and/or less severe side effects than those associated with current therapies would be particularly beneficial.
Since some onychomycosis infections may require up to a year of treatment for healthy, non-infected nail to fully regrow, the active agent must be present at the infected site in therapeutic concentrations long enough to effect a cure. Such agents should also prevent relapse and re-infection after discontinuation of therapy, have minimal side effects and exhibit an acceptable safety profile. Chronic administration of either a topical or oral treatment is therefore required, and will typically last for the period of time required for new, healthy nail to regrow, which can vary on an individual basis. Treatment periods for onychomycosis generally start at several weeks to several months long and last up to a year. Chronic administration of a topical or oral antifungal drug presents unique toxicity concerns. For example, even if an active agent is deemed safe for chronic use, its topical administration must be carried out in a manner that formulates the active agent at a desired concentration and where the carrier itself is safe for chronic administration to the nail. Chronic administration of a topical composition also requires patient compliance, which can be compromised if the treatment regimen is difficult or otherwise undesirable. For example, patient compliance in the treatment of onychomycosis is more likely to be compromised if the pharmaceutical composition has any one or more of the following features: is sticky or has an unpleasant texture, irritates the nail or surrounding skin, leaves an uncomfortable film on the nail, is messy to apply (e.g., when its application results in ‘run-off’ in which the composition does not stay on the nail and uncontrollably rolls or seeps off the nail and onto the surrounding skin), has a bad odor, requires periodic (e.g., weekly) removal of resulting film or lacquer, and the like. Thus, in the context of chronic administration of an active agent to the nail, the safety and performance characteristics of the pharmaceutical composition containing the active agent are highly important. Chronic administration of an oral drug also requires patient compliance. In addition, chronic administration of an oral drug in the treatment of onychomycosis results in prolonged systemic exposure to the active agent, which can have adverse health consequences such as undesired drug-drug interactions with existing medications and toxicity concerns, both of which can greatly limit use in a large portion of the patient population (e.g., in elderly patients who are more susceptible to onychomycosis and also who are more likely to be on a daily regimen of other pharmaceutical agents). Patients taking oral antifungal medications should also have periodic laboratory evaluations to monitor liver and blood cell function. Elewski, B. E., supra.
Onychomycosis affects toenails substantially more than fingernails and toenails are approximately twice as thick as fingernails. The reported prevalence of toenail onychomycosis in the Western adult population is approximately 14% and increases with age. De Berker, supra. The nail plate, through which an active agent must travel to reach the site of onychomycosis infection, is dense and hard. In addition, the nail plate of a toenail is substantially thicker than the nailplate of a fingernail, providing a formidable barrier to the nail bed. In contrast to Tinea pedis treatment, in which the active agent has to pass the thin, elastic and pliable Stratum coreum (the outermost layer of the epidermis) of the skin, treatment of onychomycosis requires an active agent to pass through the hard, dense and thick nail plate of a fingernail or toenail. The natural barrier of a nail provides a harsher environment and a much longer diffusion pathway for drug delivery as compared to treatment applications that only need to penetrate the Stratum coreum of the skin, with toenails having about twice the diffusion pathway of fingernails. The physical and chemical differences between the nail and the Stratum coreum account for the unique treatment challenges for fungal infections involving the nail, especially the toenail, which are not shared by fungal infections of the skin.
Factors that contribute to the development of onychomycosis include advanced age, diabetes (which reduces circulation to the extremities), history of prior infection, wearing heat- and moisture-retaining footwear, communal bathing, immunosuppression (e.g., HIV infection, the use of antibiotics or immunosuppressive drugs), trauma to the nail, use of insufficiently cleaned manicure tools, poor overall health, and warm climates.
It is estimated that about half of those affected with onychomycosis are not receiving treatment. Medical News Today, Mar. 21, 2008. However, it is important to treat onychomycosis, as it is an infection and does not resolve spontaneously. The infection may worsen, spread to other uninfected locations (e.g., other nails or to the surrounding skin) or infect other individuals. Onychomycosis infections can greatly affect an individual's quality of life and cause pain and morbidity. Infections of the fingernails, which are plainly visible, may be cosmetically unacceptable and result in embarrassment, emotional distress, loss of self-esteem, anxiety and depression. Individuals with moderate to severe onychomycosis may experience limits in manual performance and ambulation, loosing their ability to perform many routine tasks.
Current therapies do not sufficiently or effectively meet the challenges presented by onychomycosis. Existing topical therapies for onychomycosis have low mycologic cure rates and poor complete cure rates. They can also be inconvenient to the user, requiring the daily application of a nail lacquer and weekly removal of the resulting film. Oral therapies for onychomycosis are associated with higher mycologic cure rates than existing topical therapies, but these drugs exhibit poor cure rates, are contraindicated in numerous patient populations and have been associated with severe, and even deadly, side effects. Due to the low cure rates and significant drawbacks to existing therapies, the development of new topical treatments for onychomycosis is desired. A topical treatment that results in high cure rates, provides a clear nail, has minimal side effects, and is associated with high patient compliance, is particularly desired. An effective topical treatment for onychomycosis preferably addresses each of the challenges presented by onychomycosis. The compositions and formulations described herein provide a significant solution to this problem and provide additional benefits as provided herein.
The foregoing examples of the related art and limitations are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification as provided herein.